tbuckley/cabot-search huggingface dataset:
Association of cachexia with loss of function mutations in <i>STK11/LKB1</i> for NSCLC.
Authors: Rodney E. Infante, Chul Ahn, John D. Minna, Puneeth Iyengar
Journal: Journal of Clinical Oncology (2023)

e15099 Background: Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, occurs in 50% of non-small cell lung cancer (NSCLC) patients. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. The evolving landscape of increased genomic testing of human tumors and derived cell lines has further given us an opportunity to leverage these findings to identify a genetic biomarker that regulates CC development through a novel in vivo human NSCLC cachexia screen. Methods: To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia (n = 10) or non-cachexia (n = 7). Whole exome sequencing of tumors was conducted to identify candidate cachexia-associated genes and gene variant analysis was conducted to identify gene variants that associated with NSCLC-associated CC. CRISPR/Cas9 targeted gene silencing in human NSCLC and mouse cancer lines verified if target genes conferred the cachexia phenotype. Circulating tumor DNA analysis of a 246 NSCLC patient cohort was used to confirm candidate gene variants association with cancer-related weight loss. Results: Whole exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in STK11/LKB1 (p = 2x10 -12 ), a regulator of nutrient sensor AMP kinase. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient and immunocompetent models, respectively. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines resulting in host adipose and muscle tissue wasting. Mutational analysis of circulating tumor DNA from 246 NSCLC patients identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis (OR = 17 ± 1, p = 0.004). Conclusions: The current data provides evidence that tumor STK11/LKB1 loss of function is a driver of CC in NSCLC, simultaneously serving as the first genetic biomarker for this wasting syndrome.
Radiation induced lymphopenia in unilateral versus bilateral radiochemotherapy in treatment of head and neck cancer: A retrospective case-control study.
Authors: Jerome Bendavid, Roger Sun, Pierre Blanchard, Eric Deutsch, Philippe Gorphe, Yungan Tao, France Nguyen, Ines Chaffai, Camelia Billard Sandu, Caroline Even
Journal: Journal of Clinical Oncology (2023)

e18065 Background: Grade 3+ radiation-induced lymphopenia is a frequent biological complication of external beam radiotherapy (RT) in the management of head and neck cancers, likely due to the large irradiated cervical volume. This complication has been shown to be a significant prognostic factor for mortality. The aim of this study is to evaluate the difference in lymphopenia and prognosis between unilateral and bilateral prophylactic lymph node irradiation in head and neck cancers. Methods: This is a retrospective, single center case – control study in patients who received unilateral or bilateral radio chemotherapy for head and neck cancers between 2014 and 2020. Cases (unilateral neck irradiation) were matched to controls (bilateral neck irradiation) according to initial TNM, histology, tumor location, postoperative status. The comparison of the evolution of the lymphocyte count during treatment was evaluated by univariate analysis, as well as the evaluation of the overall survival (OS) and the progression free survival (PFS) between these two groups. Another univariate analysis is used to compare OS and PFS in these two groups between patients who developed Grade 3 or higher lymphopenia during treatment and those who did not. Results: In this retrospective study, 94 patients were analyzed (n = 47 in the RT unilateral group and n = 47 in the RT bilateral group). All patients received concomitant systemic therapy. Median age was 59,3 years in the unilateral group (vs 59 years in the control group). Radiotherapy was given postoperatively in 66% vs 53.2% of patients. Squamous cell carcinoma was the most frequent histological subtype with 93,6% in each RT group. All patients were treated in Intensity modulated radiation therapy (IMRT). Median follow up was 38 months in the case group and 37,6 months in the control group. Biological data from the start of radiotherapy to day 100 posttreatment was available for 90 patients (45 in each group). A linear regression model as a function of time and lymphocyte count estimated a -0.011 G/l decrease in lymphocyte count each day and a higher lymphocyte count with unilateral neck irradiation of 0.16 G/l. This was consistent with a mixed model considering the patient as a random effect. In univariate analysis, the lymphocyte nadir was significantly higher in the unilateral group 0.30 [0.15- 0,42] vs 0.37 [0,26-0.48] p = 0,029, with no significant difference in OS and PFS between these two groups. In each of the two groups, there was no significant difference in OS and PFS according to the presence or absence of grade 3 or higher lymphopenia during the treatment. Conclusions: This study, although retrospective, showed a slight benefit on radiation-induced lymphopenia in the context of unilateral radiotherapy without negative impact on OS and PFS.
Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting fusion protein, in combination with atezolizumab in patients with advanced solid tumors.
Authors: Anwaar Saeed, Babar Bashir, Jason J. Luke, Reuven Chantre, Shira Amsili, Rinat Tabakman, Yaffa Shwartz, Adam Foley-Comer, Antonio Jimeno
Journal: Journal of Clinical Oncology (2023)

2632 Background: DSP107 is a bi-functional fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BB ligand (4-1BBL). The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and anchoring trimeric 4-1BBL to the tumor, which interacts with 4-1BB expressed on activated immune cells. This results in proliferation and conditional activation of effector cytotoxic T-cells in the tumor microenvironment. Thereby, DSP107 triggers both innate and adaptive immune responses. Phase 1 monotherapy dose escalation data demonstrated an excellent safety profile with no binding to red blood cells and no dose limiting toxicities (DLTs), hematological or hepato-toxicities. Here we describe data from the completed DSP107 plus atezolizumab combination dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (1, 3 or 10 mg/kg; N = 6-7 patients/dose cohort) and atezolizumab (1200 mg) Q3W during 3-week treatment cycles. The primary objective was to determine the safety and tolerability of DSP107 in combination with atezolizumab. Restaging imaging was performed every two months and evaluated by RECIST v1.1 criteria. Results: In 19 patients, DSP107 with atezolizumab was well tolerated with no DLTs. Grade 1-2 treatment related adverse events (AEs) were observed in 68% of patients (13/19). The most frequent AEs included diarrhea (21%), fatigue (21%), infusion related reaction (IRR; 16%), nausea, decreased appetite, arthralgia, myalgia and Grade 1 anemia (11% each). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. Stable disease (SD) as best response was observed in 8/19 (42%) patients with treatment duration currently up to 10.5 months. At the highest dose of DSP107 (10 mg/kg), 3/7 patients had SD (1 microsatellite stable-colorectal cancer (MSS-CRC) patient with KRAS mutation had 16% target lesion shrinkage and no progression for 7 months). An additional 2 patients with advanced MSS-CRC (with BRAF and KRAS mutations, respectively) demonstrated deep and durable responses (-73 and -76% reduction in target lesions) including disappearance of pulmonary and hepatic target lesions in one patient. These patients currently continue to receive treatment after &gt; 8 and &gt; 6 months, respectively. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. These Phase 1 data suggest that the combination of DSP107 with PD(L)1 blockade may have anti-tumor activity in cold tumors such as MSS-CRC. Clinical trial information: NCT04440735 .
BREAKWATER: An open-label, multicenter, randomized, phase 3 study, with a safety lead-in (SLI), of first-line (1L) encorafenib (E) + cetuximab (C) ± chemotherapy (CT) vs standard-of-care (SOC) CT for BRAF V600E-mutant metastatic colorectal cancer (mCRC).
Authors: Scott Kopetz, Takayuki Yoshino, Tae Won Kim, Harpreet Singh Wasan, Eric Van Cutsem, Fortunato Ciardiello, Timothy S. Maughan, Cathy Eng, Rona Yaeger, Jayesh Desai, Xiaosong Zhang, Tiziana Usari, Ave Mori, Josep Tabernero
Journal: Journal of Clinical Oncology (2023)

TPS3627 Background: Globally, 8-12% of patients (pts) with mCRC have BRAF V600E mutations, which confer poor prognosis. Based on BEACON (NCT02928224), EC was approved for the treatment (tx) of previously treated pts with BRAF V600E-mutant mCRC. BREAKWATER (NCT04607421) is evaluating EC ± CT vs SOC CT in pts with BRAF V600E-mutant mCRC. In the BREAKWATER SLI (N = 57), EC + CT showed encouraging antitumor activity. Confirmed ORR by BICR (95% CI) with EC + mFOLFOX6 and EC + FOLFIRI, respectively, was 68.4% (46.0, 84.6) and 75.0% (46.8, 91.1) in 1L, and 37.5% (13.7, 69.4) and 44.4% (24.6, 66.3) in 2L. mPFS by BICR (95% CI) with EC + mFOLFOX6 and EC + FOLFIRI, respectively, was 11.1 months [mo] (8.5, NE) and NE (13.8, NE) in 1L, and 10.8 mo (4.3, NE) and 12.6 mo (6.9, NE) in 2L. These results support the continued evaluation of EC + CT. Based on the SLI, EC + mFOLFOX6 was selected for the phase 3 portion. Here we present the updated study design. Methods: BREAKWATER is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating 1L EC ± CT vs SOC CT alone in pts with BRAF V600E-mutant mCRC. Approximately 620 pts will be enrolled in the phase 3 portion and an additional 135 in cohort 3 (Table). Phase 3 and cohort 3 inclusion criteria are age ≥16 (or ≥18 based on country); no prior systemic tx for metastatic disease; measurable disease (RECIST 1.1); BRAF V600E-mutant mCRC (blood or tumor tissue); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Pts who received prior BRAF or EGFR inhibitors, those with symptomatic brain metastases (unless stable for ≥4 weeks prior to randomization), or with MSI-H/dMMR tumors (unless ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition) are excluded. Study treatments and endpoints are shown in the Table. Phase 3 enrollment began in November 2021. Clinical trial information: NCT04607421 . [Table: see text]
Potential improvement in the diagnostic accuracy in detecting the estrogen receptor status in metastatic and recurrent breast cancer using 18F-FES PET/CT in the US.
Authors: Adolfo Fuentes-Alburo, Nicholas DiGregorio, Kurt Neeser, Jiran Jin, Regina Young
Journal: Journal of Clinical Oncology (2023)

3063 Background: ER status helps classify BC for the most appropriate treatment pathway. Biopsy (Bx) and immunohistochemical (IHC) are established procedures to determine the ER status in metastatic BC (mBC, i.e., first occurrence of metastases) and recurrent BC (rBC, i.e., progression of mBC). In some cases, the accuracy of Bx/IHC to inform ER status may be challenged (e.g. difficult to access lesions; ER discordance within/across lesions and due to temporal heterogeneity; and when a Bx fails to obtain representative tissue). 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) is a radiolabeled form of estrogen that binds to ER. For use with positron emission tomography /computed tomography imaging (PET/CT), it allows an assessment of whole-body ER+ status. In prospective trials and meta-analyses, 18F-FES PET/CT provided high diagnostic accuracy (DA) of ER+ disease. This study evaluated the potential increase in accuracy in determining ER+ status when 18F-FES PET/CT was added to IHC in mBC and rBC. Methods: An Excel based decision model was developed to estimate the impact on DA for ER+/HER2- US mBC and rBC patients over a five-year period by introducing 18F-FES PET/CT. The model assumed that 18F-FES PET/CT was added to Bx/IHC to classify ER status in three cases: (i) for mBC patients when Bx failed or was inconclusive, (ii) for mBC patients when Bx was not possible, or (iii) for all rBC patients. The DA between two scenarios was compared: scenario A, DA of Bx/IHC only and scenario B, 18F-FES PET/CT + Bx/IHC. Results: Scenario B, adding 18F-FES PET/CT, may lead to an increase in the initiation of appropriate endocrine- and chemotherapies, as defined by clinical practice guidelines, in all comparisons. The largest increase in DA was in rBC and, when BX is not possible, in mBC patients. Also, results indicate that introducing 18F-FES PET/CT decreases the number of re-biopsies performed except when Bx was not possible (ii). Conclusions: Adding 18F-FES PET/CT to Bx/IHC is expected to improve the DA of a patients’ ER status thereby increasing the information available to inform treatment, thus reducing the need for re-biopsies in mBC and rBC patients. By far the largest increase in DA of ER status using 18F-FES PET/CT was seen among patients with rBC (iii). [Table: see text]
Capecitabine-oxaliplatin (CAPOX) prior to chemoradiotherapy (CRT) and surgery in magnetic resonance imaging (MRI)-defined poor-risk rectal carcinoma (PRRC): A single center experience.
Authors: Carla Bellido Ribes, Jorge Soler, Nuria Ruiz, Silvia Rubio Novella, Virginia Morillo, Jorge Molina, Isabel Busquier Hernandez
Journal: Journal of Clinical Oncology (2023)

e15638 Background: Clinical trials have studied the efficacy and safety of neoadjuvant chemotherapy (CT) and CRT in PRRC. Chau published his data on PRRC studied with MRI: tumors within 1 mm of mesorectal fascia, T3 at or below levators, tumors extending &gt; 5 mm into perirectal fat, T4 and T1-4N2 tumors (JCO 2006; 245: 668-674). Following this strategy, we present the data from our center. Methods: between February 2006- July 2018 we treated 77 PT with MRI-defined PRRC with CAPOX x 4 cycles, Capecitabine-radiotherapy, surgery and capecitabine 4 cycles (Chau strategy). Results: Our sample includes 43 men and 34 women, median age 59 (range 31-77). A patient died after the first CAPOX due to a hemorrhagic stroke. 69 PT had symptomatic improvement with CT, without identifying any progression. Surgery has performed in 75 PT and 65 had R0 resection, R1 in 6 patients, R2 in 2 patients and 2 lost. On an intent-to-treat analysis, pathological complete responses was achieved in 13 (pCR: 16,9%) of patients. The mean number of lymph nodes removed was 11. 51 patients (66,2%) started CT post-surgery. With a median follow up of 113 months [range 24-199],26 patient (33,8%) presented disease progression, 5 local and 21 distant recurrence. There were 14 deaths due to disease progression. 5-years OS was 87% (CI 95%: 79,4-94,6%) and DFS was 80,2 (CI 71-89,4%). Conclusions: Our data support the rutine use of CAPOX and following CRT prior to surgery on PT with PRRC, with promising results consistent with published trial data.
Blood-based DNA methylation panel for the early diagnosis of lung cancer.
Authors: Rongxi Yang, Feifei Di, Mengxia Li, Yining Yang, Hongli Yuan, Jialie Jin
Journal: Journal of Clinical Oncology (2023)

e20551 Background: Early detection of lung cancer (LC) is vital for reducing of LC-related mortality. Although the screening of persons at high risk for LC by low-dose computed tomographic (LDCT) has showed an inspiring 20.0% decrease in mortality, it also comes along with a dramatically high false positive rate for distinguishing the malignant nodules from the benign nodules. Thus, it is necessary to develop a diagnostic tool with high discriminant ability for identifying malignant nodules. Methods: The methylation levels of five candidate genes were quantitatively measured via mass spectrometry. A diagnostic model was developed by blood-based methylation levels in training cohort (650 LC cases vs. 114 benign lung nodules), and further validated the performance in validation cohort (195 LC cases vs. 39 benign lung nodules) by binary logistic regression. Notably, 91.8% LC cases were collected at Stage I. Results: The methylation model of 35 CpG sites was developed and validated for LC diagnosis. This model achieved a sensitivity of 85.4% and a specificity of 92.5% in training cohort [Area Under the Curve (AUC): 0.945], and a sensitivity of 84.1% and a specificity of 97.2% in validation cohort (AUC: 0.932). The performance was well maintained in (a) Stage I subgroup (n = 447), with a sensitivity of 82.6% and a specificity of 81.6%; (b) nodule diameter ≤ 1 cm (n = 113), with a sensitivity of 80.6% and a specificity of 81.6% in validation cohort. Conclusions: This study suggests that the blood-based DNA methylation panel may provide the potential utility for early diagnosis of LC cases, which would promote early diagnosis and benefit more LC patients.
Efficacy and safety of BRAF/MEK inhibitor rechallenge in patients with advanced melanoma: Systematic review and meta-analysis.
Authors: Jonathan N. Priantti, Maysa Vilbert, Thiago Madeira, Francisco Cezar A Moraes, Erica C. Koch Hein, Ludimila Cavalcante
Journal: Journal of Clinical Oncology (2023)

e21535 Background: Approximately 50% of patients with melanoma harbor a BRAF mutation and are eligible for targeted therapy (TT) with BRAFi/MEKi. In spite of a response rate of nearly 70%, roughly half of patients will progress within a year due to development of resistance. Rechallenging patients with BRAFi/MEKi may be an alternative to overcome resistance and improve outcomes. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BRAFi/MEKi rechallenge in patients with advanced melanoma. Methods: PubMed, Scopus, the Cochrane Library, ASCO publications, ESMO, and AACR databases were searched for relevant studies. Rechallenge was defined as patients treated with BRAFi/MEKi that developed disease progression or had significant adverse effects and went on an interval treatment or drug holiday, before being reintroduced to BRAFi/MEKi. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with the I(2) statistics and random-effect model was used to pool studies. Results: Seven studies met inclusion criteria, with a total of 400 patients. The medium follow-up ranged from 6.8 to 15.7 months. Elevated LDH was seen in 48.5% (194/400) of patients, and 53% (164/310) had brain metastases (BM). Prior to rechallenge, 83% (333/400) of patients received immunotherapy as interval treatment, mainly anti-PD-1 and/or anti-CTLA-4, and 10% (40/400) were on a drug holiday. During the rechallenge, 79% (317/400) of patients were treated with the combination of BRAFi/MEKi, whereas 21% (83/400) were treated with BRAFi alone. In a pooled analysis, the median PFS was 5 months (95% CI 4.0 – 5.9), and median OS was 9.8 months (95% CI 9.3 – 20.4). The 1-year OS rate was 42.63% (95% CI 30.25 - 55.02). ORR was 34.25% (95% CI 28.50 - 40), and DCR was 65.01% (95% CI 57.31 - 72.72). Prognostic markers such as BM and elevated LDH were not statistically significant. Treatment was well tolerated without unexpected adverse events. Conclusions: This meta-analysis indicates that advanced melanoma patients with refractory disease benefit from rechallenge with BRAFi/MEKi, particularly from high DCR, with a promising effect on 1-year OS rate. Further randomized controlled trials are warranted to investigate these findings. [Table: see text]
Under-screened: COVID-19 lockout measures and the reduction of early-stage cancer patients’ consultations in Argentina.
Authors: Ernesto Gil Deza, Gaston Martin Reinas, Liliana D. Gonzalez, Isaias Gil Deza, Monica Montiel, Carlos Garcia Gerardi, Mariana Abal, Claudia Lorena Acuna, Leonel Smolje, Francisca Rojas, Juan Pollola, Marcelo Muino, Eduardo L. Morgenfeld, Edgardo G. J. Rivarola, Daniela Gercovich
Journal: Journal of Clinical Oncology (2023)

e18801 Background: The COVID-19 pandemic caused a disruption in health services, specifically in cancer prevention, during quarantine. Argentina had one of the most extensive social isolation policies, which began on March 20, 2020. We analyzed the pandemic’s impact on the number of new patients and tumor stage distribution for those seen between March 20, 2020 and March 18, 2021 (Group B = Pandemic) and compared it with: i) those seen in the previous five years (Group A = Pre-pandemic); and ii) those seen between March 20, 2021 and December 31, 2022 (Group C = Post-pandemic). Methods: Our database comprised all new patients admitted to Henry Moore Cancer Institute (IOHM) in Buenos Aires, Argentina between March 20, 2015 and December 31, 2022. It included population characteristics at the time of first consultation, diagnosis and tumor stage according to TNM AJCC (8th Edition). The comparisons were made through Statistical t-Test and Chi-square homogeneity test. Results: Between March 20, 2020 and December 31, 2022, 17833 new patients were admitted to IOHM. The distribution of diagnoses was similar for all three groups: Breast (23%), Colorectal (11%), Prostate (10%), Gynecological (9%), Lung (7%), Renal (5%), Lymphomas (5%), Cervix (4%), Head and neck (3%), Pancreas (2%), Melanoma (2%), Sarcomas (2%), others (17%). Table 1 summarizes our main findings. The incidence of in situ tumors (stage 0) showed a significant reduction during the first year of COVID-19 in five tumors, despite strong evidence for screening benefits in all of them: Breast, Colorectal, Prostate, Melanoma and Cervix. The decrease in stage I new patients was observed in virtually all tumors, as well as the relative increase in stage IV (most notable in lung cancer, colorectal cancer and melanoma). Conclusions: A) During the first year of the COVID-19 pandemic, there was an expected quantitative decrease in new patients compared to the previous five years. B) However, we have also found qualitative changes in the characteristics of patients seeking a first consultation: younger patients, with worse ECOG, less early stages (0 and I) and more advanced stages (III and IV) in practically all tumors. C) These figures have improved in the 22 months following the lockdowns, but have not yet recovered to the values of pre-pandemic years. D) Given the strong evidence available for screening benefits in all of the five tumors that have seen a reduction in early stages consultation, preventative actions and campaigns must be reinforced. [Table: see text]